Anacetrapib: a new approach to cardiovascular risk reduction

Anacetrapib, a novel CETP inhibitor: pursuing a new approach to cardiovascular risk reduction.

Literature - Gutstein DE et al; Clin Pharmacol Ther. 2012 Jan;91(1):109-22.

Gutstein DE, Krishna R, Johns D, Surks HK, Dansky HM, Shah S, Mitchel YB, Arena J, Wagner JA.

Clin Pharmacol Ther. 2012 Jan;91(1):109-22. doi: 10.1038/clpt.2011.271.


Cholesteryl ester transfer protein (CETP) inhibition is a promising experimental strategy to raise high-density lipoprotein cholesterol (HDL-C) and reduce cardiovascular risk. This review focuses on the highly selective and potent CE TP inhibitor anacetrapib and discusses the available preclinical and clinical information pertaining to it. We also describe strategies to target HDL-C, discuss the mechanism underlying CETP inhibition and its effects on lipid biology, and give an overview of other CETP inhibitors that are currently in development.


As current LDL-C reducing strategies only lead to a ~30% reduction in the risk of major cardiovascular events [1], raising HDL-C might be a promising intervention, for example by inhibition of cholesterol ester transfer protein (CETP).
Role of CETP in lipid metabolism. CETP mediates the transfer of cholesteryl ester (CE) and triglyceride (TG) between lipoproteins. The transfer of CE into apolipoprotein B–containing LDL particles contributes to the maturation of VLDL particles to more atherogenic, more readily oxidized LDL particles, which contribute to macrophage foam cell formation. ABCA1, ABCG1, and SR-BI mediate efflux of cholesterol out of the peripheral macrophage to nascent, pre-β HDL, which matures to larger HDL via the esterification of cholesterol by LCAT. CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-level density lipoprotein; LCAT, lecithin: cholesterol acyltransferase; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

Anacetrapib is a highly selective and potent inhibitor of CETP

Chemical structure of anacetrapib. In panel (a), the stick structure of anacetrapib is shown [3].
In panel (b), carbon is indicated in green, oxygen in red, nitrogen in blue, fluorine in sky blue, and hydrogen in gray

Preclinical and clinical studies have shown that anacetrapib increases HDL-C, lowers LDL-C and lipoprotein (a) and is well tolerated. The safety profile that was characterized in DEFINE does not show the off-target effects shown by torcetrapib.

Anacetrapib (N=808) n(%)
Placebo (N=804) n(%)
Prespecified adjudicated cardiovascular safety end point
15 (1.9)
21 (2.6)
Cardiovascular death
3 (0.4)
1 (0.1)
Nonfatal myocardial infarction
6 (0.7)
9 (1.1)
Unstable angina
1 (0.1)
6 (0.7)
Nonfatal stroke
5 (0.6)
5 (0.6)
Total mortality
11 (1.4)
8 (1.0)
Heart failure
2 (0.2)
4 (0.5)
8 (1.0)
28 (3.5)
Percutaneous coronary intervention
6 (0.7)
25 (3.1)
Coronary artery bypass graft
2 (0.2)
3 (0.4)
Ongoing and planned phase III studies will evaluate its effects on cardiovascular outcomes in patients at high risk for coronary heart disease and also its lipd- and lipoprotein-mediating effects in patients with dyslipidemia. The global REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) will evaluate outcome-related benefits of anacetrapib.


CETP inhibition is a promising target for improving cardiovascular outcomes in patients with dyslipidemia by lowering HDL-C. The outcomes of REVEAL are awaited to evaluate the usefulness of anacetrapib to reduce residual risk and to confirm the hypothesis that raising HDL-C results into cardiovascular benefit in patients with dyslipidemia and patients with established atherosclerotic heart disease.


1. Baigent, al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366, 1267–1278 (2005).
2. Duffy, D. & Rader, D.J. Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport. Circulation 113, 1140–1150 (2006).
3. Smith, al. Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: modifications of the oxazolidinone ring leading to the discovery of anacetrapib. J. Med. Chem. 54, 4880–4895 (2011).
4. Cannon, C.P. et al.; Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N. Engl. J. Med. 363, 2406–2415 (2010).

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